HRP950002A2 - Asymetric hydrogenation of beta- or gamma-ketoesters and beta or gamma-ketoamides - Google Patents

Abstract

beta - or gamma -Ketoesters and beta - or gamma -ketoamides are asymmetrically reduced with a Ru(II)-BINAP derived catalyst at about 40 DEG C. and about 50N/mm2 of hydrogen in the presence of a strong acid.

Description

This is a partial continuation of the pending application Ser. But. 07/922,355 filed Jul. 13, 1992.

This invention relates to a new process in which it has been shown that in the presence of trace amounts of strong acid, asymmetric hydrogenation proceeds at low temperatures and pressures that can be easily achieved, with substrate/catalyst ratios up to about 10,000. The reaction can be carried out at pressures less than or equal to 150 psi, and as such the reaction does not require special equipment to carry out the reaction and can be carried out in half-drive volume.

Another aspect of this invention is a simple reproducible process for obtaining a purified catalyst. This invention also relates to the identification of the catalyst responsible for carrying out this process.

Asymmetric hydrogenation using the Ru(II)-BINAP or Ru(II)-t-BINAP system (ruthenium complexes 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or 2,2'-bis(di -p-tolylphosphino)-1,1')-1,1'-binaphthyl) introduced by Noyori et al., provides high enantioselectivity over a wide range of substrates with outstanding turnover (Noyori et al., Acc. Chem.. Res. 23, 345 (1990)). However, all reports relating to the reduction of β-cotoesters (Noyori et al., J. Am. Chem. Soc., 109, 5856 (1987)) have the disadvantage that temperatures higher than 80°C or higher hydrogen pressures are required of 6895N/mm2, where special apparatus is required (Kitamura et al., Tetrahedron Lett., 32, 4163 (1991); Taber et al., Tetrahedron Lett., 32, 4227 (1991), Keck et al., J. Org. Chem., 56, 6606 (1991)).

Short description of the pictures

Picture 1.

250 Mhz 1H NMR /(C2H5)2NH2/+/Ru2Cl5((R)-BINAP)2/-•CH3Ph in CD2Cl2 at room temperature.

Figure 2.

Expansion of the 3.0 ppm to 3.5 ppm region of the 400.13 Mhz 1H NMR /(C2H5)2NH2/+/Ru2Cl5((R)-BINAP)2/-•CH3Ph in CD2Cl2 at -40°C. (a) is the full coupled spectrum of this region; (b) is the decoupled spectrum of this region obtained from the irradiation of the peak at 8.53 ppm; and (c) is the decoupled spectrum of this region obtained from the irradiation of the peak at 1.41 ppm.

A new procedure for the asymmetric reduction of β- or γ-ketoesters or β- or γ-ketoamides involves the addition of a chiral ruthenium BINAP or t-BINAP catalyst, for example /(C2H5)2NH2/+/Ru2Cl5/(S)-BINAP/2/- , /(C2H5)2NH2/+/Ru2Cl5/(S)-t-BINAP/2/-, /RuCl(PhH)(BINAP)/Cl or /RuCl(PhH) (t-BINAP)/Cl catalysts in solution β - or γ-ketoester and β- or γ-ketoamide in C1-3 alkanol, primarily methanol, followed by addition of a strong acid and reduction to β- or γ-ketoester and β- or y-ketoamide by stirring in the presence of hydrogen.

[image]

where is:

R1 is normal or branched C1-C4 alkyl;

X is O or NR 5 ;

Y is C(R2)2 or a single bond

R2 is: H, or normal or branched C1-C6 alkyl,

R3 is: H, normal or branched C1-C6 alkyl, CH2NHCOR6, or R1 and R3 taken together form a lactone or cyclic amide of 5 to 7 atoms, one of which is oxygen or nitrogen,

R4 is

[image]

[image]

R3 and R4 taken together form a ring of 5 to 7 carbons, in which R3 R4 represents a carbon chain of 3 to 5 carbons;

R5 is H normal or branched C1-C4 alkyl, or CO2C1-C4 alkyl, and

R6 is normal or branched C1-C4 alkyl, or O-C1-C4 alkyl, phenyl, O-benzyl.

Abbreviations

BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

t-BINAP 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl

BINAP in this application represents all chiral ligands of 2,2'-bis(diarylphosphino)-1,1'-binaphthyl and it is understood that although the specific stereochemistry is not stated, that the ligand used is either R- or S- antipode. The selection of the R- or S-BINAP ligand will determine the stereochemistry of the β- or γ-hydroxyesters and β- or γ-hydroxyamides that are obtained.

An asterisk is used to represent the specific enantiomer depending on the stereochemistry of the BINAP used.

1 N/mm2 is equivalent to approximately 0.145 psi

Boc t-butyloxycarbonyloxy

MS methanesulfonyl

COD cyclooctadienyl

om overlapping multiplet (from English overlapping m).

The amount of catalyst in relation to the amount of substrate above about 0.02 mol % is not critical, and excess catalyst will not seriously affect the yield and enantiomeric purity, but amounts up to about 0.1 mol % are completely adequate.

The concentration of the substrate in the alkanol is primarily about 0.5 to about 2.25 M, although the concentration is not critical. It is convenient to deoxygenate the alkanol solution before the reduction, for example by passing nitrogen for several minutes.

The strong acid used in the new process is about 0.1 to 10 mol% HCl, H2SO4, H3PO4, CH3SO3H, or the like, preferably HCl, H2SO4, or CH3SO3H.

The reaction mixture is mixed by shaking or stirring and reduction is achieved at about 40-50°C and a hydrogen pressure of about 50 to about 1400 N/mm2 until the required hydrogen uptake is achieved, usually in about 3-8 hours. Under the conditions described above, enantiomeric excess > 97% is routinely achieved for the achiral starting β- or γ-ketoester and β- or γ-ketoamide chiralane.

There is a dramatic dependence of the reaction on low levels of strong acid. A reaction mixture of β- or γ-ketoester, or β- or γ-ketoamide and acid-free catalyst was exposed to 345 N/mm2 (50 psi) of hydrogen at 50°C for 24 hours without hydrogen uptake. When 1 mol % HCl was added, the reaction was brought to completion within 3 hours. Sulfuric acid was just as effective. Notably, the /RuCl(PhH) ((R)-BINAP)/cl catalyst, which does not contain endogenous amines, also exhibits this acid dependence. A very low concentration of acid after neutralization of any basic impurities is required for maximum reaction speed. Any further increase in acid concentration does not provide an improvement in speed.

The catalyst is easily obtained using standard anaerobic techniques from commercially available (cyclooctadiene)ruthenium dichloride. Filtration of the product using a double-sided filter provides the pure product, (C2H5)2NH2/+/Ru2Cl5(-BINAP)2/- as a solvate, such as benzene, toluene, xylene, chlorobenzene or 1,2-, 1,3- or 1, 4-dichlorobenzene, etc.

Asymmetric reduction of β-ketoester to the corresponding enantiomerically pure β-hydroxyester is an important synthetic step in the synthesis of a number of important useful chemical products such as:

1. Immunosuppressive agent, FK-506 (Jones et al., J. Org. Chem., 54, 17-19 (1989));

2. "Colletal" (Keck et al., J. Org. Chem., 56, 6606-6611 (1991));

3. "Carnitine" (Carnitine) (Tetrahedron Letters, 29 1555-1556 (1988));

4. "Statin" (Statin) (Nishi et al., Tetrahedron Letters, 29, 6327-6330 (1988);

5. "Gleosporin" (Schreiber et al., J. Amer. Chem, Soc., 110, 6210-6218 (1988)):

Another important type of product that includes the asymmetric reduction of β-ketoester in its synthesis is a group of carbonic anhydrase inhibitors, which are effective locally in the treatment of ocular hypertension and glaucoma related to this. This class of compounds has a general structure:

[image]

or pharmaceutically acceptable salts thereof, wherein R is C 1-5 alkyl; and R 1 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy-C 1-3 alkyl and are described in U.S. Pat. Patent No. 4,797,413, issued January 10, 1989. The series of steps in the synthesis described below for a topical carbonic anhydrase inhibitor, where R is defined as n-propyl, and R' is defined as methoxypropyl, is representative of the process of this invention.

[image]

[image]

The novel process of this invention is described as 2→3 in the above reaction scheme. The enantiomerically pure alcohol obtained in this step is responsible for introducing the optical activity of the carbonic anhydrase inhibitor. Its activation and displacement with inversion provides optically pure 5, which can be cyclized to the key intermediate 6 containing the carbon skeleton of these compounds.

The following examples further illustrate the use of this process for the preparation of compounds of formula 1 and the use of this catalyst in this process and, as such, should not be considered or construed as limiting the invention set forth in the appended claims.

Example 1

Obtaining a catalyst

[image]

[image]

Step A: Obtaining /(C2H5)2NH2/+/Ru2Cl5((R)-BINAP)2/-•CH3Ph Structure 12

(Cyclooctadienyl)ruthenium dichloride (214 mg, 0.76 mmol) and (R)-BINAP (500 mg, 0.80 mmol) were charged to a 50 mL round-bottom flask and connected to a double-sided filter (Kontes #215500-6044) with the flask. with a 100 ml round bottom at the opposite end. Vacuum lubricant is used to ensure an air-tight joint. Rubber bands were a simple and efficient way to connect the apparatus. The entire apparatus is evacuated and filled with nitrogen. Dry toluene (17 ml) and dry triethylamine (1.7 ml), which are deoxygenated with a stream of nitrogen in the course of several minutes, are added via the lower side arm. The flask is closed and the mixture is heated to 140°C, whereby a dark brick-red solution is obtained. After 4 hours, the apparatus is allowed to cool to room temperature with vigorous stirring while the catalyst settles. The apparatus is vented to nitrogen and switched to filter the product using vacuum on the lower side arm, and the nitrogen on the upper The precipitate is washed with deoxygenated toluene (17 ml) and the filtrate flask is replaced with an empty flask. 31P NMR shows that the filtrate contains the desired product. The entire apparatus is placed under vacuum and the product is dried overnight, yielding 470 mg. (75%) dark red solid:

1H NMR (CD2Cl2, 400.13 MHz) δ 8.53 (broad s, 2H), 8.07 (t,J=8.8 Hz, 4H), 7.82 (t, J=8.3 Hz, 2H), 7.65 (m, 6H), 7.55 ( m, 4H), 7.47 (m, 4h), 7.4-7.1 (m, 18H), 6.95 (m 2H), 6.84 (t, J=7.4 Hz, 2H), 6.8-6.7 (om, 4H), 6.7- 6.6 (om, 4H), 6.6-6.5 (OM, 12H), 3.24 (broad m, 6H), 2.3 (s, 3H), 1.45 (t,, J=7.3 Hz, 9H)/ see Figure 1 for 1H NMR spectrum/; 31P NMR (CD2Cl2, 161.98 MHz), δ 56.5 (d, J=38.0 Hz), 52.3 (D, j=38.0 Hz);

Analysis calculated for C99H84Cl5NP4Ru2:

C 66.39, H 4.73, N 0.78, Cl 9.90, P 6.92

Found C 66.06, H 4.74, N 0.74, Cl 9.79, P 9.91

Decoupling and peak experiments undoubtedly confirm the presence of diethylammonium ions. At -40°C methylene protons of diethylammonium appear as two multiplets at 3.2 ppm /See Figure 2(a) for 1H NMR spectrum/. When the triplet at 1.4 ppm is irradiated, the signal at 3.2 ppm appears as two triplet doublets /See Figure 2 (c) for the 1H NMR spectrum/. When the broad singlet at 8.53 ppm is irradiated, the signal at 3.2 ppm appears as two quartet doublets /See Figure 2 (b) for the 1H NMR spectrum/. When diethylamine is added to the solution, the signal at 3.2 ppm merges with the diethylamine signal. Triethylamine did not cause this behavior.

[image]

[image]

Step B: Preparation of Ru2Cl5((R)-BINAP)2 Structure 13

Catalyst 12 (12 mg, 6.7 μmol) was charged into a hermetic NMR tube (obtained from Wilmad) which was evacuated and refilled with nitrogen. Dry methylene chloride-d2 (0.8 ml) is deoxygenated by passing nitrogen through it for 2 minutes. It is added by means of a fine needle while partially uncapping the tube while passing nitrogen through the stopper, flushing the air from the tube inlet. The atmosphere above the solvent is immediately purged by careful evacuation and refilling with nitrogen. Catalyst dissolution is assisted by using sonication or a vortex mixer. Methanesulfoacid (4 μl, 62 μmol) is added to give the desired product:

1H NMR (CD2Cl2, 400.13 MHz) δ 8.14 (d, J=7.9 Hz, 2H), 8.10 (d,d, J=9.1.1.6 Ha, 2H), 7.73 (d, J=7.9 Hz, 2H), 7.65 (t, J=7.5 Hz, 2H), 7.59 (m, 2H), 7.55-7.35 (om, 22H), 7.26-7.09 (om, 18H), 6.82-6.77 (om, 4H), 6.15 (m, 4H ), 6.05 (d, J=8.7Hz, 2H), 5.83 (dd, J=8.7 Hz, 2H), 5.83 (dd, J=12.3, 7.9Hz 4H), 6.15 (m, 4H), 6.05 (d, J=8.7 Hz 2H), 5.83 (dd, J=12.3, Hz 7.9Hz 4H);

31P NMR (CD2Cl2, 161.98 MHz), δ 62.6 (d, J=40.3 Hz), 13.7 (d, J=40.3 Hz);

[image]

[image]

Step C: Preparation of Ru2Cl5((R)-BINAP)2 (H2)2 Structure 14

The sealed NMR tube containing 13 is placed under a hydrogen atmosphere by evacuating and filling with hydrogen at an increased pressure of 8 psi. To ensure saturation of the solution, the tube is placed on a vortex mixer while attached to the pipeline and mixed for 10 minutes.

1H and 31p spectra show that the hydrogen addition product (adduct) is a mixture of conformational and configurational forms.

1H NMR (CD2Cl2, 400.13 MHz) δ 8.2-5.8 (om), -9.85, -10.08, -10.2, -10.88 -11.12, -11.52;

31P NMR (CD2Cl2, 161.98MHz) δ 58.8 (d, J=29.7 Hz), 56.2 (d, J=30.4 Hz), 55.1 (d, J=32.4 Hz), 54.9 (d, J=31.7 Hz), 51.7 (d, J=29.7 Hz), 50.9 (d, J=31.0 Hz), 50.5 (d, J=31.1 Hz), 48.5 (d, J=31.7 Hz), 47.2 (d, J=30.4 Hz), 46.7 (d, J=33.1, Hz), 46.4 (d, J=32.4 Hz), 44.9 (d, J=31.0 Hz),

The following experiments showed that types 13 and 14 are active catalysts:

Methyl acetoacetate (20 μl) and methanol (100 μl) are added to the above mixture, and the NMR signals for species 14 immediately disappear, and overnight, the hydroxy product is isolated.

Examination of the (S)-Mosher ester of methyl 4-hydroxybutyrate shows that the product is in > 905 enantiomeric excess.

Example 2

/(C2H5)2NH2/+/Ru2Cl5((R)-BINAP)2/=•toluene

[image]

50 mg of 8s)-t-BINAP 1, 197 mg of RuCl2/COD/n polymer 2, 1.4 ml of Et3N and 17 ml of degassed toluene are charged into a 50 ml round-bottomed flask. The flask is closed and heated to 140°C for 6 hours. The dark red homogeneous solution was cooled to room temperature and the solution was concentrated under reduced pressure to 8 ml. Then 12 ml of heptane is added and the solution is stirred for one hour. The ruthenium polymer is precipitated and filtered through a double-sided filter. The homogeneous solution is concentrated under reduced pressure to 8 ml. Then 12 ml of haptan is added and the solution is stirred for one hour. The catalyst is precipitated and filtered using a two-sided funnel ("schlenk" product).

The precipitate was dried under vacuum to give 300 mg of a light yellow solid in 55% yield.

Example 3

/(C2H5)2NH2/+/Ru2Cl5((R)-BINAP)2/=•xylene

(Cyclooctadienyl)ruthenium dichloride (2.14 g, 7.6 mmol) and (R)-Binap (5.00 g, 8.0 mmol) were charged to a 50 mL round-bottom flask fitted with a double-sided filter (Kontes #215500-6044) with a round-bottom flask. with a 1000 ml bottom at the opposite end. Vacuum lubricant is used to ensure a hermetic connection. The entire apparatus is evacuated and filled with nitrogen. Dry xylols (170 ml) and dry triethylamine (17 ml) are added via the lower side arm, which are deoxygenated with a stream of nitrogen in the course of several minutes. The mixture is heated to 140°C, whereby a dark brick-red colored solution is obtained. After 4 hours, the apparatus is allowed to cool to room temperature with vigorous stirring until the catalyst settles. The apparatus is turned on the filter to filter the product using vacuum on the lower side of the arm and nitrogen on the upper side. The precipitate is washed with deoxygenated xylene (17 ml), and the flask containing the filtrate is replaced with an empty one. The entire apparatus is placed under vacuum and the product is dried overnight to yield 440 mg (69% dark red solid).

1H NMR (CD2Cl2, 400.13 MHz) δ 8.07 (t, J=8.8 Hz, 4H), 7.82 (t, J=8.3 Hz, 2H), 7.6 (m, J=8.3 Hz, 6H), 7.55 (m, 4Hz ), 7.47 (m, 4Hz), 7.4-7.1 (om, 20 Hz), 6.95 (m, 2H), 6.84 (t, J=7.4, 2Hz), 6.8-6.7 (om, 4H), 6.7-6.7 ( om, 4H), 6.6-6.5 (om 12H), 3.24 (m, 6H), 2.5-2.3 (3 singlet, 6H), 1.45 (t, J=7.3 Hz, 9H);

31P NMR (CD2Cl2, 161.98MHz) δ 56.5 (d, J=38.0 Hz), 52.3 (d, J=38.0 Hz).

Example 4

t-butyl 3-hydroxy-6-methoxy hexanoate

[image]

Grade A: t-butyl 3-keto-6-methoxy hexanoate (Ketoester 2)

The methyl acetoacetate dianion, obtained with sodium hydride and n-butyl lithium in THF at -15°C, is alkylated with 1.2 equivalents of bromomethyl methyl ether. The reaction proceeds in 6-8 hours to a level of 3 wt.% of the remaining starting material and is treated with methyl t-butyl ether (MTBE) and saturated ammonium chloride solution. The remaining methyl acetoacetate (m.p. 159°C) is removed by washing the crude product with four to seven volumes of xylene, whereby an alkylated ketoester containing < 0.25 wt 5 methyl acetoacetate is provided in 73-77% yield.

The methyl ester is reesterified to the t-butyl ester in 95:5 -toluene:t-butanol by refluxing the solvent through 5A molecular sieves. The boiling point of the solvent mixture is 107-111°C, well above the boiling point of t-butanol, which can be slowly lost from the flask and must be replaced as needed. After concentration, the t-butyl ester is obtained in 95% yield with <1% methyl ester remaining.

Step B: Preparation of t-butyl 3-hydroxy-6-methoxy hexanoate (β-hydroxyester 3)

The hydrogenation catalyst /(C2H5)2NH2/+/Ru2Cl5((R)-BINAP)2/- is not commercially available and must be obtained from /RuCl2(COD)/n and (R)-BINAP (see Example 1). Batches of twenty grams each are available in a 1-liter balloon. The use of a double-sided filter enables convenient isolation of the product in this volume. The catalyst, which can be handled and measured in air, should be stored under nitrogen.

Asymmetric reduction of ketoester 2 is carried out in methanol at 45°C under 1034 n/mm2 (150 psi) hydrogen with 0.09 mol% (0.4 wt. %) /(C2H5)2NH2/+/Ru2Cl5((R)-BINAP)2/ -. The reaction mixture should be deoxygenated with nitrogen and the balloon well evacuated and flushed with nitrogen before pressurizing with hydrogen. The reaction is exothermic and requires periodic cooling to maintain the temperature at 45°C. After 4 hours, hydrogen uptake is complete) and the catalyst is precipitated with hessane and filtered again. Concentration provides >97% yield of alcohol, whose enantiomeric excess was determined to be >97% by proton NMR analysis of the derived Mosher ester.

The hydrogenation reaction is very sensitive to the presence of basic impurities and it is necessary to acidify these with small amounts of strong acid.

Reesterification can occur during the reaction either from high temperatures or from the presence of excess amounts of acid. Therefore, the reaction temperature should be kept at 45°C and the minimum possible amount of HCl should be used.

Example 5

tert-Butyl 3(R)-hydroxybutyrate

[image]

tert-Butyl acetoacetate /15/ (14.5 g, 90 mmol) and methanol (30 ml) were mixed and deoxygenated with a stream of nitrogen for 5 minutes in a covered Parr shaker with a baffle. The catalyst obtained as described above (36 mg, 0.02 mmol) was added together with 2N HCl (0.041 ml, 0.082 mmol). The mixture is transferred to a standard Parr shaker and flushed with evacuation and refilling with nitrogen and then several times with hydrogen. The apparatus is heated to 40°C with shaking under 50 psi of hydrogen. After 20 minutes, the reaction becomes a homogeneous clear yellow solution that takes up hydrogen in the course of approximately eight hours. During this time the reaction was complete and the mixture was cooled and diluted with hexane (30 ml) to settle the catalyst, which was filtered. The filtrate is concentrated to give tert-butyl 3(R)-hydroxybutyrate /16/ (14.5 g, 97%).

Example 6

tert-Butyl 3(R)-hydroxybutyrate

Following the procedure described in Example 3, except that 2N HCl is replaced by 2N H2SO4 tert-butyl acetoacetate is reduced to the title product.

Example 7

[image]

In a 25 ml round-bottomed flask with a septum, β-ketoamide 17 (1 g) was dissolved in methanol (4 ml). The solution is deoxygenated with nitrogen for 20 minutes and then finely powdered /(C2H5)2NH2/+/Ru2Cl5((S)-BINAP)2/-catalyst (15.5 mg) (obtained as described in Example 1) is added. The solution is degassed with nitrogen for 5 minutes and 2N hydrochloric acid (0.092 ml) is added. The mixture is transferred through a tube into the reactor under pressure. The apparatus is heated to 60°C with shaking under 40 psi of hydrogen for 20 hours.

After 20 hours, the reaction mixture is removed from the reactor under pressure. The reactor is washed with methanol (3 ml) which is combined with the reaction mixture. The solution was concentrated under reduced pressure to give an off-white solid.

The crude reaction mixture gave an 87:13 R:S hydroxy ester ratio. The yield was 100%.

Example 8

[image]

The HCl salt of β-ketoamide 19 (1) is dissolved in methanol (16 ml) in a 25 ml round-bottom flask with a septum.

The solution is deoxygenated with nitrogen for 20 minutes and then finely divided /(C2H5)2NH2/+/Ru2Cl5((S)-BINAP)2/- catalyst (20.2) mg (obtained as described in Example 1) is added. The solution is degassed with nitrogen for 5 minutes and 2N hydrochloric acid (0.120 ml) is added. The mixture is transferred through a tube into the reactor under pressure. The apparatus is heated to 60°C with shaking under 40 psi of hydrogen for 20 hours. After 20 hours, the reaction mixture is removed from the reactor under pressure. The reactor is washed with methanol (3 ml), which is combined with the reaction mixture. The solution was concentrated under reduced pressure to an off-white solid. The crude reaction mixture gave a 97:3 R:S hydroxy amide ratio.

The yield was 80%.

Example 9

[image]

In a 25 ml round-bottomed flask with a septum, dissolve β-ketoamide mesylate 21 (0.957 g) in methanol (2.5 ml). The solution was deoxygenated with nitrogen for 20 minutes and then /(C2H5)2NH2/+/Ru2Cl5((S)-BINAP)2/- catalyst (11 mg) (obtained as described in Example 1) was added. The solution is degassed with nitrogen for 5 minutes and 2N hydrochloric acid (0.020 ml) is added. The mixture is transferred through a tube into the reactor under pressure. The apparatus is heated to 40°C with stirring under 150 psi of hydrogen for 20 hours.

After 20 hours, the reaction mixture is removed from the reactor under pressure. The reactor is washed with methanol (3 ml), which is combined with the reaction mixture. The solution was concentrated under pressure to an off-white solid. The crude reaction mixture gives a ratio of 91:9 R:S hydroxide mesylate, The yield was 80%.

Example 10

(R)-Trans-2-Methoxycarbonylcyclopentanol

2-Methoxycarbonyl-cyclopentanone (4.26 g) was dissolved in methanol (5 ml) and 0.1 ml of 1N HCl was added. The mixture was deoxygenated, 1 (36 mg) was added and the mixture was exposed to hydrogen at 40 psi and 40°C in a Parr shaker. After 6 hours, the reaction was complete, providing one product (4.10 g) in >95% excess.

1H NMR (CDCl3, 250 MHz), 4.40 (q, J=7.5 Hz, 1H), 3.71 (s, 3H), 2.65 (q, J=7.2 Hz, 1H), 2.1-1.5 (m, 6H).

Example 11

Methyl 3-hydroxy-2-methylbutyrate

Methyl 2-methylacetoacetate is hydrogenated under the conditions outlined in Example 2 or 3, whereby a 6:4 mixture of trans:cis products is obtained. The enantiomeric excess of the major isomer was >97%.

Example 12

Methyl 5-(R)-hydroxyvelerate

A mixture of methyl levulinate (10.0 g, 77 mmol), methanol (10 ml) and concentrated HCl (0.4 ml) was deoxygenated by passing nitrogen for 2 minutes. /(C2H5)2NH2/+-/Ru2Cl5((R)-BINAP)2/- (50 mg) was added and the mixture was placed in a standard Parr shaker. After evacuation and nitrogen flushing three times, the mixture is evacuated and exposed to 40 psi hydrogen pressure at 40°C for 48 hours. The solvent was removed in vacuo to give the product (9.90 g, 99% yield) which was identical to the commercially available (Aldrich) racemic pattern as determined by 1 H NMR. The optical purity was shown to be 99:1 by obtaining a proton NMR spectrum of the product (1 ml) and (S)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol (27 mg) in CDCl 3 . The determination of the peaks was performed using peaks with a racemate sample. Methyl 5-(R)-hydroxyvelerate is spontaneously lactonized, whereby 5-(R)-γ-valerolactone is obtained.

Example 13

Ethyl 3-hydroxybutyrate

This is obtained from ethyl acetoacetate in ethanol according to the procedure from Example 4 or 5. The measured enantiomeric excess was 97%.

1H NMR (CDCl3, 250 MHz) 4.20 (m, 1H, 4.10 (q J=7.5 Hz, 1H9, 2.51 (m, 2H), 1.2 (m, 5H).

Claims (17)

1. Procedure for asymmetric hydrogenation of β- or γ-ketoesters or β- or γ-ketoamides of the structural formula: [image] to obtain β- or γ-hydroxyester or β- or γ-hydroxyamide of formula I: [image] where R 1 is straight or branched C 1 -C 4 alkyl; X is O or NR 5 ; Y is C(R 2 ) 2 or a single bond; R 2 is H, or straight or branched C 1 -C 6 alkyl; R 3 is H, straight or branched C 1 -C 6 alkyl, CH 2 NHCOR 6 , or R1 and R3 together form a lactone or cyclic amide with 5 to 7 atoms, one of which is oxygen or nitrogen; R4 is [image] [image] R 3 and R 4 together form a ring with 5 to 7 carbon atoms, in which R 3 and R 4 represent a carbon chain of 3 to 5 carbon atoms; R 5 is H, straight or branched C 1 -C 4 alkyl, or CO 2 C 1 -C 4 alkyl; and R6 is straight or branched C1-C4 alkyl, or O-C1-C4 alkyl, phenyl, O-benzyl; indicated that it comprises the reaction of β- or γ-ketoester or β- or γ-ketoamide in C1-C3 alkanol with Ru(II)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (Ru(II )-BINAP) as a derived catalyst in the presence of a strong acid at 40-50°C and 500 to 14,000 bar (50 to 1400 N/mm2) of hydrogen. 2. The method according to claim 1, characterized in that it includes the asymmetric reduction of β-ketoester or β-ketoamide of the structural formula: [image] to obtain β-hydroxyester or β-hydroxyamide formulas: [image] wherein X, R1, R2, R3 and R4 are as defined in claim 1. 3. The method according to claim 1, characterized in that Ru(II)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (Ru(II)-BINAP) is a derived catalyst [(C2H5)2NH2]+ [Ru2Cl5(2,2'-bis(diphenylphosphine)-1,1'-binaphthyl)2)]- solvate. 4. The method according to claim 3, characterized in that the solvate is selected from the group consisting of benzene, toluene, xylene, chlorobenzene, or 1,2-, 1,3-, or 1,4-dichlorobenzene. 5. Process according to claim 4, characterized in that the C1-3 alkanol is methanol. 6. The method according to claim 5, characterized in that the β-ketoester concentration in the reaction mixture is 0.5 to 2.25 molar. 7. The method according to claim 6, characterized in that the amount of catalyst is 0.02 to 0.1 mol %. 8. The method according to claim 7, characterized in that the strong acid is selected from the group consisting of HCl, H2SO4, or CH3SO4. 9. The method according to claim 8, characterized in that the concentration of the strong acid is 0.1 to 10 mol %. 10. The method according to claim 9, characterized in that the strong acid is HCl. 11. The method according to claim 1, characterized in that it serves for the asymmetric reduction of β-ketoesters of the structural formula: [image] to obtain the β-hydroxyester formula: [image] wherein R1 and R4 are as defined in claim 1 and R2 and R3 are H. 12. The method according to claim 11, characterized in that it serves for the asymmetric reduction of β-ketoesters of the structural formula: [image] to obtain the β-hydroxyester formula: [image] where is: R1 methyl, ethyl, or t-butyl; R 2 and R 3 are H; you R 4 is CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 OCH 3 , or R 3 and R 4 together form a ring of 5 carbon atoms, in which R 3 and R 4 represent a carbon chain of 3 carbon atoms. 13. The method according to claim 1, characterized in that it serves for the asymmetric reduction of β-ketoamide of the structural formula: [image] to obtain β-hydroxyamide formulas: [image] wherein R1, R4 and R5 are as defined in claim 1 and R2 and R3 are H. 14. The method according to claim 13, characterized in that it serves for the asymmetric reduction of β-ketoamide of the structural formula: [image] to obtain β-hydroxyamide formulas: [image] where is: R1 methyl, ethyl, or t-butyl; R 2 and R 3 are H; you R4 is [image] 15. A compound, indicated by the fact that it has the structural formula: [image] or its solvates, where P∩P represents 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl(BINAP) or 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl( t-BINAP). 16. A compound, indicated by the fact that it has the structural formula: [image] or its solvates, where P∩P represents 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl. 17. A compound, indicated by the fact that it has the structural formula: [image] or solvates thereof, where P∩P represents 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl.